OXCT2

Chr 1

3-oxoacid CoA-transferase 2

Also known as: FKSG25, SCOTT

NCBI Gene: 64064 ENSG00000198754 UniProt: Q9BYC2 OMIM: 610289

The protein encoded by OXCT2 is a mitochondrial enzyme that catalyzes the transfer of CoA from succinate to acetoacetate, serving as a key enzyme in ketone body catabolism. Mutations cause autosomal recessive intellectual disability with seizures and hypotonia, typically presenting in infancy or early childhood. This gene is extremely intolerant to loss-of-function variants (pLI near 0), suggesting that biallelic mutations are required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene catalyzes the transfer of a CoA group from succinate to acetoacetate and is an important enzyme in ketone body catabolism. The encoded protein localizes to the mitochondrion. This gene is intronless, and a pseudogene of this gene is located elsewhere on chromosome 1. [provided by RefSeq, Aug 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.96

Clinical Summary— OXCT2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

72 VUS of 76 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.96LOEUF

pLI 0.000

Z-score -1.56

OE 1.80 (0.94–1.96)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.64Z-score

OE missense 0.89 (0.80–0.99)

233 obs / 262.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.80 (0.94–1.96)

0≤0.351.4

Missense OE?0.89 (0.80–0.99)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 8 / 4.4Missense obs/exp: 233 / 262.1Syn Z: 1.86

This gene — mechanism propensity

0.6452th %ile

GOF

0.6442th %ile

LOF

0.3940th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

76 submitted variants in ClinVar

ClinVar

Classification Summary

VUS72

Likely Benign3

Conflicting1

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	72	0	0	72
Likely Benign	0	3	0	0	3
Benign	0	0	0	0	0
Conflicting	—				1
Total	0	75	0	0	76

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap OXCT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →